Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renin have been sought as agents for control of hypertension and hyperaldosteronism.
The present invention concerns a series of novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, and hyperaldosteronism, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
Structurally the compounds of the instant invention represent a new class of peptides, in that they contain an amino acid bearing an .alpha.-heteroatom directly attached to the amino acid backbone. The positions of the various amino acids may be designated by reference to the octapeptide which is the minimal angiotensinogen sequence cleaved by renin, namely: ##STR2##
A designation for the compounds of this invention is illustrated below. The STA is considered to occupy the P.sub.1 --P.sub.1 ' positions. For example ##STR3##
The compounds of this invention have the .alpha.-heteroatom amino acid at the P.sub.2 position. It is surprising to find good activity in these compounds.